Cattley R C, DeLuca J, Elcombe C, Fenner-Crisp P, Lake B G, Marsman D S, Pastoor T A, Popp J A, Robinson D E, Schwetz B, Tugwood J, Wahli W
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Regul Toxicol Pharmacol. 1998 Feb;27(1 Pt 1):47-60.
The purpose of the workshop "Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?" was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-activated receptor (PPAR-alpha). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or in in vitro studies with human hepatocytes, although PPAR-alpha is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose-response curve at the point of departure, the background exposure levels, and variability in the human response.
“过氧化物酶体增殖性化合物对人类是否具有肝癌致癌风险？”研讨会的目的是对过氧化物酶体增殖与肝癌发生之间关系的当前科学现状进行综述。关于过氧化物酶体增殖剂可能在大鼠和小鼠中诱发肝肿瘤的机制以及这些事件是否在人类中发生，一直存在很多争论。该研讨会的一个主要目标是确定在相对于潜在人类风险评估来解释这些数据方面可能达成共识的地方。在易受其肝癌致癌作用影响的啮齿动物品系中，已确定了一组核心的生化和细胞事件，包括过氧化物酶体增殖、脂肪酰辅酶A氧化酶水平升高、微粒体脂肪酸氧化、过氧化氢过量产生、细胞增殖速率增加以及过氧化物酶体增殖物激活受体（PPAR-α）α亚型的表达和激活。尽管PPAR-α在人类肝脏中的表达水平非常低，但在接触过氧化物酶体增殖剂的人类肝脏活检中或在对人肝细胞的体外研究中尚未临床鉴定出此类效应。在细胞增殖以及PPAR-α受体表达和激活在肿瘤形成中的重要中介作用方面达成了共识。将一种化合物表征为过氧化物酶体增殖性肝癌致癌物所需考虑的必要信息包括肝肿大、细胞增殖增强以及肝脏酰基辅酶A氧化酶和/或棕榈酰辅酶A氧化水平升高。鉴于大多数过氧化物酶体增殖剂缺乏遗传毒性潜力，而且人类似乎可能对致癌反应具有抗性或不敏感，基于肿瘤数据进行风险评估可能并不合适。然而，关于中间终点的非肿瘤数据将提供适当的毒理学终点，以确定一个起始点，例如LED10或NOAEL，这将是暴露边际（MOE）风险评估方法的基础。MOE评估中要考虑的相关因素将包括起始点处剂量反应曲线的斜率、背景暴露水平以及人类反应的变异性。
